Vascular injury promotes the influx of inflammatory cells and induces apoptosis in vascular smooth muscle cells and endothelial cells. Our studies will examine the mechanisms that control the viability of both inflammatory and vascular cells and assess the consequences of these processes on vascular lesion formation. As in the original grant, studies will predominantly focus on the Fas/Fas ligand regulatory system. This research involves the construction of new animal models and performing mechanistic studies to delineate the signaling mechanisms that control the expression of apoptosis-regulatory molecules. To more fully understand the regulation and role of apoptosis in vessel wall lesion formation we propose the following specific aims: 1) Characterize a new mouse line that lacks functional Fas ligand and apolipoprotein E genes and serves as a model of accelerated atherosclerosis that is associated with autoimmune disease. 2) Characterize a new mouse line that overexpresses Fas ligand on the vascular endothelium 3) Produce and characterize new mouse models of atherosclerosis where Fas is disrupted in specific cell types. 4) Perform mechanistic analyses on the signaling and transcriptional regulators that control the sensitivity of vascular endothelial cells to Fas-mediated apoptosis. PERFORMANCESITE(S) (organization,city, state) BOSTON UNIVERSITY MEDICAL CAMPUS, BOSTON, MA KEY PERSONNEL. See instructions. Usecontinuationpagesas neededto providetherequiredinformation intheformat shownbelow. Startwith Principal Investigator.List all other key personnelin alphabeticalorder,last namefirst. Name Organization Role on Project KENNETH WALSH BUSM P.I. KAORI SATO BUSM POST-DOC YOSHIAKI TANIYAMA BUSM POST-DOC ANN BIALIK BUSM TECHNICIAN TAMAR APRAHAMIAN BUSMfTUFTS GRADUATE STUDENT JIANG YANG BUSM/TUFTS GRADUATE STUDENT DisclosurePermissionStatement. Applicableto SBIR/STTROnly. See instructions. [] Yes [] No PHS 398(Rev. 05/01) Page _2 Form Page 2 D Number_aclesconsecutively at the bottom throughout the application.Do not usesuffixessuchas 3a,3b. " Principal Investigator/Program Director (Last, first, middle): WALSH, KENNETH The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page, RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,